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JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, , VOL. 78, NO. 4, 2021, , ª 2021 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION, PUBLISHED BY ELSEVIER, , THE PRESENT AND FUTURE, JACC HISTORICAL BREAKTHROUGHS IN PERSPECTIVE, , Myocardial Revascularization Surgery, JACC Historical Breakthroughs in Perspective, Michael J. Mack, MD,a John J. Squiers, MD,a Bruce W. Lytle, MD,a J. Michael DiMaio, MD,a Friedrich W. Mohr, MDb, ABSTRACT, Coronary artery bypass grafting (CABG) was introduced in the 1960s as the first procedure for direct coronary artery, revascularization and rapidly became one of the most common surgical procedures worldwide, with an overall total of, more than 20 million operations performed. CABG continues to be the most common cardiac surgical procedure performed and has been one of the most carefully studied therapies. Best CABG techniques, optimal bypass conduits, and, appropriate patient selection have been rigorously tested in landmark clinical trials, some of which have resolved controversy and most of which have stoked further debate and trials. The evolution of CABG cannot be properly portrayed, without presenting it in the context of the parallel development of percutaneous coronary intervention. In this Historical, Perspective, we a provide a broad overview of the history of coronary revascularization with a focus on the foundations,, evolution, best evidence, and future directions of CABG. (J Am Coll Cardiol 2021;78:365–83) © 2021 by the American, College of Cardiology Foundation., , C, , urrently available treatment options for cor-, , revascularization,, , onary artery disease (CAD) include medical, , necessary to lay the groundwork (Central Illustration)., , decades, , of, , innovation, , were, , therapy, percutaneous coronary interven-, , Beginning in the early 20th century, evolution in the, , tion (PCI), and coronary artery bypass grafting, , understanding and treatment of angina pectoris par-, , (CABG). Many studies have demonstrated favorable, , alleled technologic improvements facilitating surgery, , outcomes of CABG compared with medical therapy, , on the coronary arteries until the underlying princi-, , or PCI, but CABG procedure volumes have been grad-, , ples of these developments were unified in the CABG, , ually declining for several decades (1). Nevertheless,, , procedure. Several early methods of surgical inter-, , CABG remains the most common operation per-, , vention for the relief of angina did not directly, , formed by cardiac surgeons and one of the most, , address revascularization of the coronary system., , commonly performed operations in the United States, , Surgical sympathectomy was first performed in 1916, , (2). In this Historical Perspective, we provide a broad, , by Thomas Jonnesco, whose patient had complete, , overview of the history of coronary revascularization, , relief of angina (3). In the 1930s, surgical thyroidec-, , with a focus on the foundations, evolution, best evi-, , tomy was evaluated in euthyroid patients with inca-, , dence, and future directions of CABG., , pacitating chest pain as an attempt to decrease the, , FOUNDATIONS OF, , metabolic workload of the heart with some success, , SURGICAL REVASCULARIZATION, , (4), although this approach was eventually shifted to, medical induction of hypothyroidism (5)., , Before CABG could become the first widely used and, , In 1880, Ludwig Langer had demonstrated devel-, , standardized method of achieving surgical coronary, , opment of collateral circulation around coronary, , Listen to this manuscript’s, audio summary by, Editor-in-Chief, Dr. Valentin Fuster on, , From the aBaylor Scott & White Health, Dallas, Texas, USA; and the bLeipzig Heart Center, Leipzig Germany., , JACC.org., , Vinod Thourani, MD, served as Guest Associate Editor for this paper. Javed Butler, MD, MPH, MBA, served as Guest Editor-inChief for this paper., The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’, institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,, visit the Author Center., Manuscript received December 22, 2020; revised manuscript received April 1, 2021, accepted April 8, 2021., , ISSN 0735-1097/$36.00, https://doi.org/10.1016/j.jacc.2021.04.099, Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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366, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , ABBREVIATIONS, , plaques in human subjects and proposed a, , AND ACRONYMS, , form of coronary bypass using vessels of, adjacent thoracic organs (6). Subsequently,, , BIMA = bilateral internal, , several techniques to achieve such collater-, , mammary artery, , CABG = coronary artery bypass, , alization, and thus relieve angina, were, , grafting, , developed. Pericardial abrasion was shown to, , CAD = coronary artery disease, , encourage, , vascularization, , of, , ischemic, , myocardium by Moritz et al in 1932 (7). This, , EVH = endoscopic vessel, harvesting, , technique was closely followed by attempts, , HCR = hybrid coronary, , at external collateralization of the myocar-, , revascularization, , dium with pectoral muscle, greater omen-, , LAD = left anterior descending, , tum,, , artery, , jejunum (8)., , LIMA = left internal mammary, artery, , The, , lung, , parenchyma,, , next, , historical, , and, , pedicled, , development, , was, , addressing a potential role of the left and, , LM = left main coronary artery, LVEF = left ventricular ejection, fraction, , right, , internal, , mammary, , arteries, , (LIMA/, , RIMA) to relieve angina symptoms, though, not initially via direct coronary revasculari-, , MI = myocardial infarction, MIDCAB = minimally invasive, , HIGHLIGHTS,
Coronary artery bypass graft (CABG), surgery was the first intervention for, coronary artery disease associated with a, survival benefit over medical therapy in, randomized trials and is the most common cardiac operation, with more than 20, million procedures performed worldwide.,
CABG is particularly beneficial for patients with complex multivessel disease,, left main disease, diabetes, and left, ventricular systolic dysfunction.,
The future role of CABG surgery will, depend on continued improvements in, technique, bypass conduits, and, emerging evidence., , zation. In 1939, Davide Fieschi was the first to, ligate the RIMA, a procedure which was, , separately reported coronary patch angioplasty tech-, , subsequently, , IMA, , niques (17,18). In 1958, F. Mason Sones inadvertently, , (BIMA) ligation with initial reports of nearly, , discovered coronary angiography and subsequently, , universal efficacy for relief of angina (9)., , developed this as a standard technique to obtain, , intervention, , However, early enthusiasm was dampened, , images of coronary anatomy and objectively assess, , RCA = right coronary artery, , by 2 randomized trials that demonstrated no, , severity of coronary disease (19). This was a key, , RCT = randomized controlled, , difference, , development in producing coronary bypass surgery, , trial, , among patients undergoing BIMA ligation, , and, , RIMA = right internal, , versus those who underwent sham proced-, , recognized the possibility of bypassing the obstruc-, , mammary artery, , ures (10,11). In 1946, Arthur Vineberg per-, , tions, , SVR = surgical ventricular, , formed his eponymously named procedure in, , reconstruction, , important in the development of CABG was William, , which the LIMA was “transplanted” into the, , Proudfit, who followed Sones’s patients and demon-, , anterior wall of the left ventricle, adjacent to, , strated the incremental worsening survival of single-,, , the left anterior descending artery (LAD) but, , double-, and triple-vessel disease and left ventricular, , without creating a surgical anastomosis (12)., , impairment, thereby setting the stage for stratifying, , direct coronary artery bypass, , NCDR = National, Cardiovascular Data Registry, , PCI = percutaneous coronary, , STS = Society of Thoracic, Surgeons, , TECAB = totally endoscopic, coronary artery bypass, , in, , modified, , to, , symptomatic, , bilateral, , improvement, , coronary, , intervention., , demonstrated, , by, , Sones, , immediately, , angiography., , Also, , very, , This technique theoretically facilitated col-, , CAD that is present even in studies done today (20). It, , lateralization between the LIMA and LAD, and patent, , was not until the SYNTAX (Synergy Between Percu-, , Vineberg grafts have been demonstrated 30 years af-, , taneous Coronary Intervention With Taxus and Car-, , ter the index implantation (13). Those LIMA implants, , diac Surgery; NCT00114972) trial in 2009 that a formal, , that were open many years later had connections to, , stratification was devised, and even the SYNTAX, , coronary arteries that could actually be seen angio-, , score, , graphically. That is to say, the Vineberg implant did, , stratification., , is, , not, , totally, , unrelated, , to, , Proudfit’s, , not supply blood to muscular syncytium, but rather to, visible coronary arteries., , THE ADVENT OF CABG, , As the surgical approach to angina was evolving,, several other technical innovations occurred, without, , In the early development of CABG, a major step for-, , which CABG would have been neither feasible nor, , ward was the importance of understanding the, , successful. Alexis Carrel developed vascular anasto-, , physiology of CAD. There were 2 important recogni-, , mosis techniques in canines, for which he was ulti-, , tions. First was that the death and disability associ-, , mately awarded a Nobel Prize in Physiology or, , ated with CAD are related to the obstructions in the, , Medicine in 1912 (14). John and Mary Gibbons worked, , coronary arteries limiting blood flow to an area of, , for decades to invent the heart-lung bypass machine,, , myocardium under some circumstances. While that, , with first in-human applications by the 1950s (15)., , may seem obvious to us today, it was still not clear at, , Bailey et al reported successful in-human coronary, , the time. It was thought by some that myocardial, , endarterectomies (16), while Senning and Effler, , infarction (MI) may be a muscular process and not, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Mack et al., Surgical Coronary Revascularization, , C ENTR AL I LL U STRA T I O N Landmark Developments in the History of Coronary Artery Bypass Grafting, , Mack, M.J. et al. J Am Coll Cardiol. 2021;78(4):365–83., , A timeline of the important contributions to the operative procedure., , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 367

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368, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , related to the obstructions in the arteries. Second was, , improvements in technique, keener patient selec-, , the recognition that in most patients the obstructions, , tion, and the introduction of myocardial protection,, , tended to be worse proximally rather than being, , post-CABG, , randomly distributed throughout the coronary ar-, , improved. Nevertheless, the widespread prolifera-, , teries. This observation made bypass surgery likely to, , tion of CABG was questioned, especially given that, , make the blood supply more secure and provided a, , early comparative trials failed to demonstrate any, , theoretical basis for the operation., , survival benefit of CABG over medical therapy (31), , No single surgeon can properly take credit for, performing the “first” in-human CABG, but rather a, , morbidity, , and, , mortality, , greatly, , except in the subgroup of patients with left main, (LM) disease (32)., , series of operations performed by several surgeons, each made important contributions to the establish-, , EARLY TRIALS: CABG VERSUS MEDICAL THERAPY, , ment of CABG as a standardized surgical procedure, (21). In 1960, Robert Goetz completed a RIMA to right, , The initial study of CABG came in the form of 3 large, , coronary artery (RCA) bypass using tantalum rings to, , randomized controlled trials (RCTs) in the 1970s: the, , perform the anastomosis (22). Two years later, David, , Veterans Administration (VA) Cooperative Study, , Sabiston performed the first hand-sewn coronary, , (33), the European Coronary Surgery Study (34), and, , anastomosis, using saphenous vein graft (SVG) to, , the Coronary Artery Surgery Study (CASS) (Table 1), , bypass the RCA, but he did not report this attempt, , (35). These were the first RCTs to be performed in, , until 1974 because the patient died a few days after, , the management of CAD. Because percutaneous, , surgery (23). Garrett and DeBakey performed the first, , treatment of CAD began only in 1977, these trials, , LAD bypass, also using SVG, in 1964 as a bailout, , randomized patients to CABG or medical therapy, , procedure in a 42-year old patient but did not report, , alone., , this case until 1973 after 7 years of follow-up (24). The, , The VA Cooperative Study enrolled 1,015 patients, , Russian surgeon Vasilii Kolesov, who also in 1964, , with angina that had failed medical management and, , performed a RIMA-RCA bypass but published his, , had angiographic evidence of CAD ($50% stenosis of, , experience in 1967, is often credited with performing, , at least 1 major coronary artery) from 1970 to 1974., , the first successful planned hand-sewn CABG anas-, , The study found that patients with LM disease un-, , tomosis (25). Finally, George Green performed the, , dergoing CABG had a survival benefit over medical, , first LIMA-to-LAD bypass, the first, and still only,, , therapy alone, but that this survival benefit was not, , surgical technique to have reached the status of being, , evident in any other subgroups after 4 years of, , a quality indicator in the performance of any opera-, , follow-up (33)., , tion in 1968 (26)., , The European Coronary Surgery Study random-, , At the Cleveland Clinic, Rene Favaloro performed, , ized men with angina and angiographic evidence of, , his first CABG, an SVG interposition graft to repair an, , CAD ($50% stenosis in at least 2 major coronary, , occluded RCA, in 1967, and by 1968 he had performed, , vessels) to CABG or medical therapy from 1973 to, , more than 50 similar CABG procedures (27). Thus,, , 1976. After 5 years, there was a notable benefit in, , Favaloro is widely recognized as the surgeon having, , mortality in patients with 3-vessel disease and/or LM, , the greatest impact by demonstrating the clinical, , disease (34), a finding that persisted up to 12 years, , feasibility of CABG in its earliest days (28). Based on, , (36)., , Favaloro’s experiences, amounting to 1,700 CABG, , Finally, CASS randomized patients with angina and, , procedures from 1967 to 1970 (29), CABG performance, , angiographic evidence of CAD ($70% stenosis of RCA,, , rapidly proliferated beginning in the 1970s (30). In a, , LAD, or left circumflex; or $50% stenosis of LM) to, , 1973 report, DeBakey proudly quoted a contemporary, , CABG or medical therapy from 1975 to 1979. This trial, , news article that had declared “vein grafting will, , demonstrated no survival benefit for CABG over, , become the most frequently performed operation in, , medical therapy overall nor in any subgroups after 5, , America” (24). Indeed, annual CABG volumes grew, , years. However, there was a 5% annual rate of, , exponentially during this decade, from 30,000 in, , crossover into CABG among patients initially assigned, , 1974 to 191,000 by 1983 (8)., , to medical therapy (35)., , The earliest high-volume CABG series reported, , Although these trials did not initially identify an, , morbidity and mortality rates that greatly exceeded, , overall survival benefit for CABG over medical ther-, , what would be acceptable today. In a review of the, , apy, they established the role of CABG by demon-, , pioneering single-center CABG experiences, opera-, , strating that it could be routinely performed with an, , tive mortality ranged from 2.3% to 12%, with most, , improved safety profile and survival benefits in spe-, , centers reporting >5% operative mortality (30). With, , cific subgroups. Later, the patients enrolled in these, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , 369, , Surgical Coronary Revascularization, , T A B L E 1 Summary of Early Landmark Randomized Controlled Trials Comparing CABG Against Medical Therapy in Patients With Coronary Artery Disease and Angina, , Trial, (Ref. #), , VA Coop (33), , Study, Period, , CABG,, n, , Medical, Therapy, n, , 1972-1974, , 332, , 354, , Enrollment Criteria, , Angina $6 mo, $3 mo trial medical therapy, Angiographic evidence of $50%, stenosis of $1 major coronary, artery with distal target, , European Coronary, Surgery Study, (34), , 1973-1976, , CASS (35), , 1975-1979, , 395, , 373, , Men, age <65 y, Angina $3 mo, Angiographic evidence of $50%, stenosis of $2 major coronary, arteries with distal targets, , Notable Outcomes, , Operative mortality: 5.6%., Mortality (4 y): 14% CABG vs 17% medical therapy, (all-comers)., Mortality (4 y): 7% vs 36% (patients with LM disease)., Mortality (4 y): 15% CABG vs 14% medial therapy, (patients without LM disease)., Operative mortality: 3.6%., Mortality (5 y): 6.5% CABG vs 16% medical therapy., Mortality (5 y): 7.1% CABG vs 38% medical therapy, (patients with LM disease)., Mortality (5 y): 5.1% CABG vs 15% medical therapy, (patients with 3-vessel disease)., , LVEF >50%, 390, , 390, , Age #65 y, Canadian Cardiovascular Society, class I or II angina, , Operative mortality: 1.4%., Mortality (annual rate): 1.1% CABG vs 1.6% medical, therapy., , Angiographic evidence of $50%, stenosis of left main or $70%, stenosis of other major coronary, artery, LVEF >35%, Yusuf metaanalysis* (37), , 1972-1984, , 1,324, , 1,325, , 7 randomized controlled trials, enrolling patients with stable, angina, , Operative mortality: 3.2%., Mortality (5 y): 10.2% CABG vs 15.8% medical therapy, (all-comers)., Mortality (7 y): 15.8% CABG vs 21.7% medical therapy, (all-comers)., Mortality (10 years): 26.4% CABG vs 30.5% medical, therapy (all-comers)., Risk reduction of CABG over medical therapy most, evident in patients with LM or 3-vessel disease., , *The Yusuf meta-analysis was composed mostly of patients enrolled in these landmark trials., CABG ¼ coronary artery bypass grafting; LM ¼ left main; LVEF ¼ left ventricular ejection fraction., , trials made up the majority of patients included in an, , changed our lives as cardiovascular surgeons”—, , important meta-analysis performed by Yusuf et al in, , myocardial protection (38)., , 1994 that finally demonstrated superior survival after, CABG over medical therapy in the all-comers popu-, , MYOCARDIAL PROTECTION, , lation (37); that meta-analysis is generally credited, with catalyzing the acceptance and adoption of CABG, , Early CABG procedures were performed on ischemic, , as a therapeutic option in CAD. Importantly, these, , arrested hearts while the patients were supported on, , trials also provided the first evidence that certain, , cardiopulmonary bypass. In the 1960s, autopsy, , subgroups of patients, including those with LM dis-, , studies implicated myocardial injury as the driver of, , ease or multivessel CAD, would derive the greatest, , “low-cardiac-output syndrome,” a common cause of, , benefit from CABG. Indeed, in the same meta-, , early postoperative mortality in patients undergoing, , analysis, the superiority of CABG was particularly, , a variety of cardiac operations. Autopsies on those, , pronounced in patients with LM or multivessel, , patients were surprising to those performing them:, , disease., , Pathologists described “microinfarctions distributed, , In aggregate, these 3 landmark trials played an, important role in validating the survival benefit of, , in a patchy manner . [that] did not resemble those, seen in atherosclerotic heart disease” (39)., , surgical coronary revascularization. Perioperative, , Extensive efforts were underway to mitigate these, , outcomes were improved owing to a variety of, , deleterious consequences of ischemia and cardio-, , factors, , experience,, , pulmonary bypass via the development of myocardial, , shorter operating times, improvements in cardio-, , protection. Rapid cardiac arrest via administration of, , pulmonary bypass technology and anesthesia, and, , hyperkalemic solution was introduced by Melrose, , better patient selection (8). However, a major, , and Bentall in 1955 (40). Subsequently, David Hearse, , advancement in the performance of CABG was what, , described myocardial damage as a result of adenosine, , Favaloro declared as the “one contribution that, , triphosphate depletion and calcium overload after, , including, , greater, , surgeon, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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370, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , F I G U R E 1 Bilateral Internal Mammary Coronary Artery Bypass Grafts, , (A) Anatomic illustration; (B) 3-dimensional coronary computed tomographic angiography; (C) intraoperative view; (D) postoperative, angiogram demonstrating patent bypass grafts., , hyperkalemic arrest; in response, he developed St, , in most centers, but recently there has been a growing, , Thomas’ Hospital solution, one of several early crys-, , body of evidence that del Nido solution, initially, , talloid cardioplegic, , and, , developed for use in the pediatric population, may be, , Buckberg further delineated the consequences of, , a preferable alternative to blood cardioplegia during, , myocardial ischemia and reperfusion injury during, , isolated CABG surgery while allowing for shorter, , the 1970s and ultimately developed cold blood car-, , cardiopulmonary, , dioplegia (42). In 1983, Hearse proposed 3 founda-, , owing to its lasting cardioplegic effects and less, , tional principles of optimal cardioplegia: 1) rapid, , frequent dosing requirements (46)., , solutions, , (41). Follette, , bypass, , and, , cross-clamp, , times, , diastolic cardiac arrest to conserve energy; 2) hypothermia to slow cellular metabolism; and 3) applica-, , BYPASS CONDUITS, , tion of substances to prevent ischemic injury (43)., The development of cardioplegia strategies and, , In addition to myocardial protection, a significant, , solutions for myocardial protection were key in, , advance in the evolution of CABG was established by, , reducing perioperative MI and mortality rates. How-, , Loop and Lytle in the mid-1980s of the LIMA as the, , ever, over the ensuing decades a still-ongoing debate, , best-performing bypass graft conduit. First, they, , continued regarding which cardioplegia solution is, , demonstrated a clear superiority of the LIMA over, , best: crystalloid or blood (44)? Dozens of RCTs have, , SVG in terms of both short- and long-term patency, , been performed to compare cardioplegia strategies,, , (47). These angiographic findings were then corre-, , and none has emerged as clearly superior (45). In, , lated with improved clinical outcomes in patients, , North America, blood cardioplegia has been favored, , undergoing bypass of the LAD with LIMA rather than, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , F I G U R E 2 Techniques Related to Coronary Artery Bypass Grafting With Reversed Saphenous Vein Grafts, , (A) External view of an endoscopic vein harvest (EVH); (B) endoscopic view of EVH; (C) open vein harvest incision; (D) external stenting of, vein graft (VEST). Arrows refer to the the vein graft stent., , SVG (48). Following dissemination of these results,, , serious adoption until several decades later when, , there was a major shift in the preferred bypass graft, , improvements in harvesting techniques combined, , conduit in isolated CABG operations: LIMA utilization, , with local and systemic vasodilator therapy signifi-, , increased from 31% in 1988 to 88% by 2000 and sur-, , cantly decreased the incidence of vasospasm and, , passed 95% by 2010 (49). Currently, LIMA-to-LAD, , intimal hyperplasia that had plagued the radial artery, , bypass serves as the standard of care for CABG and is, , previously (57)., , considered to be a benchmark of quality. It is a Class I, , Multiarterial grafting has been rigorously evalu-, , recommendation in both U.S. and European guidelines, , ated in several RCTs evaluating BIMA and radial ar-, , (50,51) and is perhaps the only “settled science” in, , tery bypass graft conduits (58). None of those trials, , the field of surgical coronary revascularization., , clearly demonstrated superior outcomes associated, , Aside from the LIMA, the right gastroepiploic and, , with multiarterial grafting in terms of survival or, , inferior epigastric arteries have excellent long-term, , various composites of clinical events, although long-, , patency (52,53). However, these vessels are not, , term arterial patency rates exceeded those of SVG in, , widely used owing to the need for laparotomy during, , most of the trials., , harvesting, their fragility and vasoreactivity, and, , The, , ART, , (Arterial, , Revascularization, , Trial;, , variations in length and diameter that limit utility;, , ISRCTN46552265), in which patients were random-, , therefore, these arteries are reserved for rare cases in, , ized to single-mammary or BIMA grafting, showed no, , which IMA, radial artery, and SVG conduits are not, , difference in survival over 10 years in the intention-, , available (54)., , to-treat, , analysis, , (59)., , However,, , a, , significant, , After the LIMA, the 2 conduits with the greatest, , confounder was the high degree of crossover between, , penetrance into common practice are the RIMA and, , groups (13.9% assigned to BIMA received a single-, , radial arteries. Lytle published the first evidence that, , mammary bypass, and 21.8% assigned to the single-, , BIMA utilization, in which both the LIMA and RIMA, , mammary group also received a radial artery graft),, , are used as bypass graft conduits, had advantages, , and a post hoc as-treated analysis of the trial, , over single IMA grafting in terms of both survival and, , demonstrated that multiarterial grafting (BIMA or, , the need for reintervention (Figure 1) (55). Carpentier, , single mammary plus radial) was superior to single-, , et al first reported use of the radial artery as a bypass, , mammary grafting for mortality and a composite of, , conduit in 1973 (56), but that conduit did not gain any, , mortality, MI, and stroke (59). Similarly, no RCT, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 371

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372, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , T A B L E 2 Summary of Landmark Trials Comparing Vein Harvesting Techniques in Patients Undergoing CABG, , Trial, (Ref. #), , Study, Period, , Endoscopic, n, , Open, n, , PREVENT, IV (69), , 2002-2003, , 1,753, , 1,247, , Enrollment Criteria, , Index CABG with $2 planned, vein-graft implantations, Harvest method determined by, surgeon, Primary study: randomization of vein, grafts to ex vivo treatment or, placebo, , ROOBY, (73), , 2003-2007, , 564, , 907, , Male veterans, Index CABG, Harvest method determined by, surgeon, Primary study: randomization to, on-pump or off-pump CABG, , REGROUP, (70), , 2014-2017, , 576, , 574, , On-pump CABG with $1 planned, vein graft, Harvest technique randomized, , Notable Outcomes, , Vein graft failure (1 y): 46.7% endoscopic, vs 38.0% open (P < 0.001)., Mortality (3 y): 7.4% endoscopic vs 5.8%, open (P ¼ 0.005)., MACE (3 y): 20.2% endoscopic vs 17.4%, open (P ¼ 0.04)., , Vein patency (1 y): 74.5% endoscopic vs, 85.2% open (P < 0.0001)., Repeated revascularization (1 y): 6.7%, endoscopic vs 3.4% open (P < 0.05)., MACE (1 y): 8.5% endoscopic vs 7.2%, open (P ¼ 0.42)., No reported angiographic outcomes., MACE (3 y): 13.9% endoscopic vs 15.5%, open (P ¼ 0.47)., No differences among individual end, points from the composite., Leg wound infection: 1.4% endoscopic vs, 3.1% open., , CABG ¼ coronary artery bypass grafting; MACE ¼ major adverse cardiovascular event (composite of death, myocardial infarction, or repeat revascularization)., , evaluating single mammary plus radial artery grafting, , years and long-term results are at least a decade, , has individually demonstrated a survival benefit, , away (65)., , associated with utilization of the radial artery in lieu, , In cases where surgeons elect to use an SVG or, , of SVG, but recently published pooled meta-analyses, , radial artery, these bypass conduits were traditionally, , of, , demonstrated, , harvested via an open incision along the entire length, , improved composite outcomes associated with mul-, , 6, , underpowered, , RCTs, , have, , of the vessel, often on a pedicle to minimize conduit, , tiarterial grafting for up to 10 years (60)., , injury. Endoscopic vessel harvesting (EVH) was, , Observational data have demonstrated advantages, , developed in the 1990s to reduce the morbidity, , of multiarterial grafting over single-arterial grafting, , associated with these incisions (Figures 2A to 2C) (66)., , in terms of patency, survival, MI, and reintervention, , A consensus committee recommended EVH as the, , (61,62). However, none of these data nor the Class IIa, , standard of care in 2005 (67). EVH was rapidly adop-, , recommendations from multisociety guideline state-, , ted, and 30-day clinical outcomes of 200,000 patients, , ments in favor of multiarterial grafting (50,51,54),, , in STS database undergoing CABG from 2003 to 2008, , have prompted widespread adoption of multiarterial, , appeared to be similar between the open and EVH, , grafting. Among STS database participants, BIMA, , approaches (68)., , utilization has remained constant at 5% over the past, , However, post hoc analyses of the PREVENT IV, , decade, while radial artery utilization has decreased, , (Project of Ex-Vivo Vein Graft Engineering via, , from 7% to 5% (63)., , Transfection IV; NCT00042081) (69) and ROOBY, , A variety of factors that may explain the low, utilization, , of, , multiarterial, , grafting, , have, , (Randomized On-Off Bypass; NCT00032630) (70) tri-, , been, , als then showed that EVH was independently asso-, , posited, including additional technical difficulty,, , ciated with lower angiographic graft patency rates, , increased risk for deep sternal wound infection, and, , and increased adverse clinical outcomes compared, , a lack of compelling randomized evidence clearly, , with open harvesting. Ultimately, both trials were, , demonstrating the benefit of multiarterial grafting, , criticized for including surgeons with limited expe-, , (64). The international ROMA (Randomized Com-, , rience in performing EVH, leading to early graft, , parison of the Clinical Outcome of Single Versus, , failure (71). Another consensus panel gave a Class I,, , Multiple Arterial Grafts; NCT03217006) trial, which, , Level of Evidence: B recommendation for EVH of, , has been powered to detect differences in clinical, , SVG in 2017 based on a meta-analysis (72). This, , outcomes among single- and multiarterial (BIMA or, , recommendation was further substantiated by the, , radial artery) grafting, may further inform the field,, , REGROUP (Randomized Endovein Graft Prospective;, , but initial outcomes will not be available for several, , NCT01850082) trial, which was primarily powered to, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , 373, , Surgical Coronary Revascularization, , T A B L E 3 Summary of Landmark Randomized Controlled Trials Comparing On-Pump and Off-Pump CABG, With a Focus on 5-Year Outcomes, , Trial (Ref. #), , ROOBY (76), , Study, Period, , Off-Pump, n, , On-Pump, n, , 2002-2007, , 1,104, , 1,099, , Enrollment Criteria, , Male veterans, Urgent or elective isolated CABG, , CORONARY (77), , 2006-2011, , 2,375, , 2,377, , Urgent or elective isolated CABG, $1 risk factor: age $70 y, peripheral, arterial disease, cerebrovascular, disease or carotid stenosis, renal, insufficiency, , GOPCABE (78), , 2008-2011, , 1,179, , 1,191, , Urgent or elective isolated CABG, Age $75 y, , Notable Outcomes, , Mortality (5 y): 15.2% off-pump vs 11.9% onpump (P ¼ 0.02)., MACE (5 y): 31.0% off-pump vs 27.1% on-pump, (P ¼ 0.046)., Mortality (5 y): 14.6% off-pump vs 13.5% onpump (P ¼ 0.30)., Composite of MACE, stroke, or renal failure (5 y):, 23.1% off-pump vs 23.6% on-pump, (P ¼ 0.72)., Mortality (5 y): 31% off-pump vs 30% on-pump, (P ¼ 0.71)., MACE (5 y): 34% off-pump vs 33% on-pump, (P ¼ 0.70)., , Abbreviations as in Table 2., , detect differences between open harvest versus EVH, , Pump Coronary Artery Bypass Grafting in Elderly, , of SVGs by experienced surgeons. REGROUP demon-, , Patients; NCT00719667) (78) (Table 3). Unfortunately,, , strated no differences in major adverse cardiovascu-, , these results have collectively failed to resolve the, , lar events after 3 years of follow-up, and EVH was, , question of preferred technique., , associated with a lower risk of leg wound infection, , The ROOBY trial randomized male veterans at VA, , (Table 2) (73). Therefore, most CABG procedures per-, , medical centers to off-pump or on-pump CABG from, , formed today in the United States use EVH for SVG, , 2002 to 2007. After 5 years, those in the off-pump, , harvest. The International Society for Minimally, , cohort experienced higher rates of all-cause mortal-, , Invasive Cardiothoracic Surgery consensus also rec-, , ity and a composite of adverse cardiovascular out-, , ommended endoscopic harvest for the radial artery, , comes including death, repeated revascularization,, , (72)., , and MI (76). But the ROOBY trial has been criticized, , CARDIOPULMONARY BYPASS AND CABG, , that allowed for inexperienced off-pump surgeons to, , for a variety of design flaws—most notably, criteria, perform off-pump CABG in the trial (79)., Determination of optimal conduit(s) for revasculari-, , The CORONARY and GOPCABE trials, on the other, , zation has been a major focus, but another prominent, , hand, had much more stringent criteria regarding, , area of investigation has been on decreasing the, , prior experience for surgeons performing off-pump, , “invasiveness” of conventional CABG. A less invasive, , CABG. CORONARY randomized patients to off-pump, , approach to CABG can be implemented in 2 ways:, , or on-pump CABG from 2006 to 2011. After 5 years,, , first, by decreasing the degree of physiological insult, , there were no differences among the study cohorts,, , associated, , and, , including for all-cause mortality and a composite of, , ischemic cardioplegic arrest (off-pump CABG); and, , death, stroke, MI, new dialysis requirement, and, , second, by diminishing the degree of access inva-, , repeated revascularization (77)., , with, , cardiopulmonary, , bypass, , siveness by performing CABG through incisions, , GOPCABE also required participating surgeons to, be “experts” in off-pump surgery in order to use this, , smaller than the traditional full sternotomy., The goal of off-pump CABG, first described in 1985,, , technique (80); in this trial, elderly patients were, , is to decrease perioperative complications that lead to, , randomized to off-pump or on-pump CABG from, , long-term sequelae by avoiding the risks of cardio-, , 2008 to 2011. As with the CORONARY trial, after 5, , pulmonary bypass and aortic cross-clamping (74,75)., , years there was no difference among the study co-, , Dozens of RCTs comparing the off- and on-pump, , horts for or a composite of death, MI, and repeated, , techniques for CABG have been reported, but debate, , revascularization (78)., , over which technique should be preferred persists., , Although none of these trials demonstrated a long-, , Recently, 5-year outcomes data has been published, , term survival advantage associated with off-pump, , for 3 off-pump RCTs: ROOBY (76), CORONARY (CABG, , CABG, they were not adequately powered for such a, , Off, , Study;, , comparison. Additional data has recently emerged, , NCT00463294) (77), and GOPCABE (German Off-, , calling into question the long-term efficacy of off-, , or, , On, , Pump, , Revascularization, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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374, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , pump CABG. Multiple meta-analyses, including one, , conversion rate below 2% with acceptable long-term, , that includes 5-year data from the 3 most recent trials, , survival (88)., , (81), have associated off-pump surgery with increased, , In patients with multivessel disease, revasculari-, , hazard for mortality over the long term (82). Admin-, , zation of all cardiac territories using a minimally, , istrative claims data from more than 40,000 patients, , invasive approach, termed totally endoscopic coro-, , undergoing isolated CABG in New Jersey also suggest, , nary, , that off-pump CABG is associated with increased, , Currently, the MIST (Minimally Invasive Coronary, , rates, , of, , incomplete, , revascularization,, , artery, , bypass, , (TECAB),, , is, , also, , feasible., , repeated, , Surgery Compared to Sternotomy Artery Bypass, , revascularization, and mortality up to 10 years after, , Grafting Trial; NCT03447938) trial is randomizing, , surgery, even in the hands of experienced off-pump, , patients with multivessel CAD to full sternotomy or, , surgeons (83)., , TECAB via left anterior minithoracotomy (89)., , Whether off-pump CABG is as safe and effective as, , Recently, robotic assistance has gained some clin-, , on-pump CABG remains inconclusive, especially, , ical adoption for surgeons performing MIDCAB (90)., , among off-pump CABG advocates, but the adoption, , However, utilization of robotic MIDCAB remains low,, , rate remains relatively low. Within the STS database,, , accounting for <1% of all CABG procedures in the STS, , off-pump utilization peaked in 2008 (21% of isolated, , database (91). Most commonly, robotic assistance is, , CABGs) and has been in annual decline since (84). On, , used to facilitate harvest of the LIMA, and then a, , the other hand, off-pump CABG is the predominant, , hand-sewn anastomosis to the LAD is performed un-, , approach to surgical revascularization in other re-, , der direct vision through a left minithoracotomy., , gions of the world, even exceeding 80% of CABG, , One application that was anticipated to accelerate, , procedures in Japan (85). Without new compelling, , adoption of MIDCAB is the concept of hybrid coronary, , data, we doubt that off-pump CABG is likely to be, , revascularization (HCR). Proponents of HCR posit, , adopted any more frequently in North America. More, , that the main benefit of CABG is derived from the, , likely, off-pump CABG will remain a technique, , LIMA-to-LAD bypass, whereas SVG bypass to non-, , favored by a minority of surgeons for use in selected, , LAD vessels may not provide any advantage over, , patient groups who are most likely to benefit., , PCI in terms of long-term patency or survival., Therefore, by combining single-vessel MIDCAB and, , MINIMAL ACCESS AND HYBRID, , PCI of the non-LAD diseased territories, total revas-, , CORONARY REVASCULARIZATION, , cularization can be achieved through a more minimally invasive approach than sternotomy, while still, , The other mechanism by which the invasiveness of, , achieving the long-term benefits of the LIMA-to-LAD, , CABG can be diminished is through minimal-access, , bypass., , incisions. Limited-access approaches are possible, , However, after initial enthusiasm in the early, , because the course of the LAD along the anterior, , portion of the 2010s, during which HCR was selec-, , surface of the heart allows for LIMA-to-LAD bypass to, , tively used at up to one-third of U.S. hospitals per-, , be achieved with less than a full sternotomy. In fact,, , forming CABG (92), interest in this approach has, , Kolesov’s initial CABG operation was performed, , waned. Observational data from the National Car-, , through a left minithoracotomy (25). Starting in the, , diovascular Data Registry (NCDR) CathPCI database, , 1990s, the concept of minimally invasive direct cor-, , show that among patients with multivessel CAD, only, , onary artery bypass (MIDCAB) was refined after being, , 0.2% underwent HCR from 2009 to 2017, while nearly, , reintroduced by Valavanur Subramanian and others, , 33% underwent multivessel PCI; most hospitals, , (86,87)., , mini-, , reporting to this registry performed <1 HCR proced-, , thoracotomy and subxiphoid approaches, which can, , ure annually (93). This lack of enthusiasm for, , be performed with or without thoracoscopic assis-, , HCR was also manifest in the recent Hybrid Coronary, , tance, but the left anterolateral minithoracotomy, , Revascularization Trial (NCT03089398), in which, , approach with direct visualization is the most, , patients with multivessel CAD were randomized, , preferred technique for MIDCAB., , to HCR versus multivessel PCI; the trial was termi-, , MIDCAB, , approaches, , include, , left, , As with other evolutions in CABG technique,, , nated early owing to slow patient enrollment., , MIDCAB has been studied through RCTs. The Leipzig, , Despite the growing minimally invasive and robotic, , group has provided the best data on MIDCAB,, , experience of cardiac surgeons and trainees, wide, , demonstrating that the procedure can be performed, , adoption of MIDCAB, TECAB, and HCR remains, , with low risk of perioperative complications and a, , unlikely., , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , THE ROLE OF CABG AND PCI, , length, chronic total occlusions, and calcification and, diffuseness of disease), but not low complexity dis-, , The historical evolution of CABG cannot be fully, , ease. Recently published 10-year follow-up data from, , understood without addressing the issue of optimal, , this trial, the SYNTAX Extended Survival trial, , patient selection. The earliest RCTs, which compared, , (NCT03417050), demonstrated that in patients with 3-, , CABG against medical therapy, offered some insights, , vessel CAD, CABG remained superior to PCI in terms, , into certain patient groups most likely to benefit, , of all-cause mortality (99)., , from revascularization (33–35). Then, 15 years after, , In the BEST (Bypass Surgery Versus Everolimus-, , the introduction of CABG, Andreas Grüntzig devel-, , Eluting Stent Implantation for Multivessel Coro-, , oped percutaneous transluminal angioplasty (94)., , nary Artery Disease; NCT00997828) trial, 880 pa-, , The initial technique of balloon angioplasty was, , tients were randomized to CABG or PCI with, , followed by bare-metal stenting within a decade, , second-generation, , (95), and eventually drug-eluting stents were added, , nately, enrollment failed to accrue, and the trial, , to percutaneous coronary intervention (PCI) in the, , was stopped early with just under one-half of the, , early 2000s (96). Evidence from a series of RCTs, , planned study population. At the primary endpoint,, , comparing PCI and CABG in specific patient pop-, , there was no difference in a combination of death,, , ulations (Table 4) has led to PCI becoming the initial, , MI, or target-vessel revascularization after 2 years., , intervention in the majority of patients undergoing, , However, after a median follow-up of 4.6 years, a, , drug-eluting, , stents., , Unfortu-, , revascularization while CABG remains the gold, , statistically significant difference was evident with, , standard for revascularization in some selected pa-, , an advantage for CABG (100). The failure to enroll a, , tient groups., , fully powered study, as well as enrollment of only, , It should be noted, however, that CABG and PCI are, 2 fundamentally different procedures that treat a, , Asian patients, limits the generalizability of the, BEST trial., , different length of the coronary artery. In contrast to, , The superiority of CABG over drug-eluting PCI for, , transcatheter and surgical aortic valve replacement, , long-term survival in multivessel disease, especially, , techniques, which both use fundamentally the same, , in diabetics and/or patients with high SYNTAX scores,, , mechanistic approach to treat aortic stenosis, CABG, , has been demonstrated via meta-analysis of ran-, , and, , domized trials with a mean of 3.8 years of follow-up, , PCI, , use, , different, , approaches, , to, , address, , obstructive coronary disease. CABG, by virtue of, , (101). Similarly, among nearly 200,000 patients in, , downstream revascularization, is more protective, , the observational ASCERT (American College of Car-, , against progression of native vessel disease than PCI,, , diology Foundation–Society of Thoracic Surgeons, , because CABG bypasses a greater length of the vessel., , [STS] Collaboration on the Comparative Effectiveness, , That difference may be the reason why CABG has, , of Revascularization Strategies) study, superiority of, , been shown to prolong life expectancy and PCI has, , CABG over PCI in patients with multivessel disease, , not for patients with chronic CAD. Although in-stent, , was demonstrated (102). Using patient data from the, , restenosis is not common, this difference may, , STS and NCDR databases linked to long-term survival, , explain why PCI is still inferior to CABG in terms of, , data from Centers for Medicare and Medicaid Services, , prolonging life expectancy., , data, investigators demonstrated that CABG afforded, , MULTIVESSEL DISEASE. The SYNTAX trial random-, , a survival benefit over PCI in elderly patients (age $65, , ized 1,800 patients with 3-vessel or LM CAD to PCI or, , years) with multivessel CAD after 4 years. Critiques of, , CABG from 2005 to 2007 (97). Although the primary, , this study have pointed to the possible role of un-, , analysis combined patients with multivessel or LM, , recognized confounders in the findings. The current, , disease, a predefined secondary subgroup analysis of, , European (51) and US (103) guidelines give Class I,, , only patients with multivessel disease (n ¼ 1,085), , Level of Evidence: B recommendations, respectively,, , demonstrated an advantage of CABG over PCI after 5, , for CABG in patients with multivessel CAD, especially, , years in terms of all-cause mortality, MI, repeated, , in patients with intermediate or high SYNTAX scores, , revascularization, and a combined endpoint of death,, , and/or diabetes., , stroke, and MI (98). Stroke rates were no different, , LEFT MAIN DISEASE. The SYNTAX trial enrolled 705, , among patients undergoing PCI or CABG after 5 years., , patients with LM disease (with or without multivessel, , Importantly, the advantage of CABG was evident in, , disease). After 5 years, there was no difference in, , patients with intermediate and highly complex CAD, , major adverse cardiovascular events or all-cause, , (as graded by the SYNTAX score, which accounts for, , mortality among patients undergoing CABG or PCI,, , vessel tortuosity and bifurcation disease, lesion, , but CABG was associated with a lower risk of repeated, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 375

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Mack et al., , 376, , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , T A B L E 4 Summary of Landmark Trials Comparing CABG and PCI, , Study, Period, , CABG, n, , PCI, n, (Stent Type), , SYNTAXES, (99), , 2005-2007, , 549, , 546 (1st-gen DES), , BEST (100), , 2008-2013, , Trial (Ref. #), , Enrollment Criteria, , Notable Outcomes, , Multivessel disease, 3-vessel disease, No previous revascularization, 442, , 438 (2nd-gen DES), , Multivessel disease, No previous CABG, No PCI with DES within 1 y, , ASCERT (102), , 2004-2007, , 86,244, , 103,549 (1st-gen, DES), , Registry analysis of CathPCI and STS, ACSD databases linked to CMS, claims files, , Mortality (10 y): 21% CABG vs 28% PCI (HR:, 1.42; CI: 1.11-1.81)., MACE (4.6 y): 10.6% CABG vs 15.3% PCI, (P ¼ 0.04)., Mortality (4.6 y): 5.0% CABG vs 6.6% PCI, (P ¼ 0.30)., Repeated revascularization (4.6 y): 3.8%, CABG vs 7.1% PCI (P ¼ 0.03)., Stroke (4.6 y): 2.9% CABG vs 2.5% PCI, (P ¼ 0.72)., Mortality (4 y): 16.4% CABG vs 20.8% PCI, (RR: 0.79; CI: 0.76-0.82)., , Age $65 y, Multivessel disease (left main, excluded), Left main disease, SYNTAXES, (99), , 2005-2007, , 348, , 357 (1st-gen DES), , Left main disease, , NOBLE, (105,106), , 2008-2015, , 603, , 598 (1st-gen DES, 12%; 2nd-gen DES, 88%), , Left main disease (>50% stenosis or, fractional flow reserve #0.80), , Mortality, stroke, myocardial infarction, or, repeated revascularization (5 y): 19%, CABG vs 28% PCI (superiority, P ¼ 0.0002)., Mortality (5 y): 9% CABG vs 9% PCI, (P ¼ 0.68)., Nonprocedural myocardial infarction (5 y):, 3% CABG vs 8% PCI (P ¼ 0.0002)., Repeated revascularization (5 y): 10% CABG, vs 17% PCI (P ¼ 0.0009)., , 8EXCEL, (107,108), , 2010-2014, , 957, , 948 (2nd-gen DES), , Left main disease ($70% by, angiography, or 50%-70% if hemodynamic significance confirmed, by fractional flow reserve), , Mortality, stroke, or myocardial infarction (5, y): 19.2% CABG vs 22.0% PCI (P ¼ 0.13)., Mortality (5 y): 9.9% CABG vs 12.0% PCI, (P ¼ NS)., Any myocardial infarction (study definition; 5, y): 9.1% CABG vs 10.6% PCI (P ¼ NS)., Any myocardial infarction (Third Universal, Definition; 5 y): 4.7% CABG vs 9.6% PCI, (P < 0.05)., Repeated revascularization (5 y): 10.0%, CABG vs 16.9% PCI (P < 0.05)., , No previous revascularization, , SYNTAX score #32, , Mortality (10 y): 28% CABG vs 27% PCI (HR:, 0.92; CI: 0.69-1.122)., , Diabetes, SYNTAX (115), , 2005-2007, , 221, , 231 (1st-gen DES), , 3-vessel and/or left main disease, Medically treated diabetes, (oral or insulin), , FREEDOM, (116), , 2005-2010, , 894, , 956 (1st-gen DES), , Multivessel disease ($70% stenosis in, 2þ major coronary arteries), Left main disease excluded, , FREEDOM, Follow-On, (117), , 2005-2010, , 465, , 478 (1st-gen DES), , Extended follow-up available on, w50% of patients from original, cohort (25/140 FREEDOM centers, participating), , Mortality, stroke, myocardial infarction, or, repeated revascularization (5 y): 29.0%, CABG vs 46.5% PCI (P < 0.001)., Mortality (5 y): 12.9% CABG vs 19.5% PCI, (P ¼ 0.065)., Stroke (5 y): 4.7% CABG vs 3.0% PCI, (P ¼ 0.34)., Myocardial infarction (5 y): 5.4% CABG vs, 9.0% PCI (P ¼ 0.20)., Repeated revascularization (5 y): 14.6%, CABG vs 35.3% PCI (P < 0.001)., Mortality, stroke, or myocardial infarction (5, y): 18.7% CABG vs 26.6% PCI (P < 0.05)., Mortality (5 y): 10.9% CABG vs 16.3% PCI, (P ¼ 0.049)., Stroke (5 y): 5.2% CABG vs 2.4% PCI, (P ¼ 0.03)., Myocardial infarction (5 y): 6.0% CABG vs, 13.9% PCI (P < 0.001)., Repeated revascularization (1 y): 4.8% CABG, vs 12.6% PCI (P < 0.001)., Mortality (7.5 y): 18.3% CABG vs 24.3% PCI, (P ¼ 0.01)., , Notable outcomes are summarized with an emphasis on the longest-term data currently available., DES ¼ drug-eluting stent; PCI ¼ percutaneous coronary intervention; other abbreviations as in Table 2., , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , vascularization and a higher risk of stroke (104). After, , elevation is commonly present with CABG and is not, , 10 years, there remained no statistically significant, , prognostic of outcomes. Recently, the EXCEL in-, , difference in survival (99)., , vestigators have further explored these differences,, , The NOBLE (Nordic-British Left Main Revasculari-, , and how each definition of MI prognosticates long-, , zation Study; NCT01496651) trial randomized pa-, , term mortality; they argue that the original protocol, , tients with LM disease to CABG (n ¼ 603) or PCI with a, , definition for MI was equally prognostic for long-term, , biodegradable stent (n ¼ 598) from 2008 to 2015 (105)., , mortality after both PCI and CABG, whereas the Uni-, , The primary endpoint of this noninferiority trial was, , versal Definition was prognostic of long-term mor-, , a composite of all-cause mortality, nonprocedural MI,, , tality only after CABG (111)., , repeated revascularization, and stroke. After 5 years,, CABG was superior to PCI for the primary endpoint, , Meta-analyses, , also, , have, , been, , performed, , to, , compile both randomized (112) and high-quality, , and was associated with lower rates of nonprocedural, , observational (113) data on comparisons of CABG, , MI and repeated revascularization, with no difference, , and PCI in patients with LM disease. These analyses, , in all-cause mortality (106)., , have generally shown that CABG is favorable to PCI in, , The EXCEL (Evaluation of Xience Prime or Xience, , patients with LM disease, especially when the SYN-, , V Versus CABG for Effectiveness of Left Main Revas-, , TAX score is high. Based in part on the results of the, , cularization; NCT01205776) trial also randomized pa-, , EXCEL and NOBLE trials, the European guidelines, , tients with LM disease (limited to low or intermediate, , were updated in 2018 to give both CABG and PCI Class, , SYNTAX scores, ie, #32) to PCI with second-, , I, Level of Evidence: A recommendations in patients, , generation drug-eluting stent (n ¼ 948) or CABG, , with LM disease and low SYNTAX score, while CABG, , (n ¼ 957) (107). The primary endpoint of this non-, , was also given Class I, Level of Evidence: A recom-, , inferiority trial was a composite of all-cause mortal-, , mendations in cases of intermediate and high SYN-, , ity, stroke, and MI (including periprocedural MI). No, , TAX score (51)., , difference between CABG and PCI was evident at the, , DIABETES MELLITUS. Currently one-half of patients, , primary endpoint (107). A secondary endpoint that, , undergoing CABG in the United States have diabetes,, , included all of the composite events of the primary, , representing a 25% increase over the past 10 years, , endpoint plus repeated revascularization similarly, , (63). Three major RCTs have evaluated outcomes of, , showed no difference between CABG and PCI after 3, , PCI and CABG in diabetics with multivessel CAD:, , years. After 5 years, there remained no difference for, , BARI-2D, , the primary composite endpoint between CABG and, , Investigation in Type 2 Diabetes; NCT00006305), , PCI. There was also no difference between 5-year, , (114), a secondary analysis of SYNTAX (115), and, , rates of stroke or cardiovascular death, but CABG, , FREEDOM (Future Revascularization Evaluation in, , was associated with lower 5-year rates of all-cause, , Patients With Diabetes Mellitus: Optimal Manage-, , mortality and repeated revascularization (108)., , ment of Multivessel Disease; NCT00086450) (116)., , (Bypass, , Angioplasty, , Revascularization, , Much has already been written in attempts to, , In BARI-2D, more than 2,000 patients were ran-, , resolve the discrepant results between the NOBLE, , domized to revascularization (via PCI or CABG) or, , and EXCEL trials (109). Several differences between, , intensive medical therapy. Although no benefit for, , these 2 trials are apparent: Different stents were used, , revascularization over intensive medical therapy was, , for PCI, and there were key differences in the trials’, , evident after 5 years according to the primary anal-, , primary endpoints. Compared with the design of, , ysis, a key secondary analysis demonstrated that, , NOBLE, EXCEL excluded repeated revascularization,, , CABG was associated with a reduction in major, , an endpoint that strongly favors CABG in NOBLE, and, , adverse cardiovascular events compared with medi-, , included periprocedural MI, an event that drove the, , cal therapy, whereas PCI was not (114). Interpretation, , primary endpoint to noninferiority of PCI compared, , of these results is challenging for 2 reasons: First,, , with CABG in EXCEL (110)., , CABG and PCI were not compared head-to-head; and, , The definition of periprocedural MI used by the, , second, drug-eluting stents became available only, , EXCEL investigators has been particularly contro-, , after trial initiation and therefore only 35% of pa-, , versial. The EXCEL trial used the Society for Cardio-, , tients undergoing PCI received a drug-eluting stent., , vascular Angiography and Interventions definition of, , The prespecified analysis of outcomes in diabetic, , MI instead of the Third Universal Definition used in, , patients enrolled in SYNTAX demonstrated the su-, , most other trials. That definition, although it was, , periority of CABG over PCI. CABG was associated with, , prespecified in the study protocol, has been criticized, , decreased rates of cardiovascular mortality, repeated, , by some in that it biased the primary endpoint in, , revascularization, and a combined endpoint of major, , favor of PCI because some degree of cardiac enzyme, , adverse cardiovascular events, with no difference in, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 377

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378, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , rates of stroke over 5 years in all tertiles of SYNTAX, , between CABG with and without SVR in the primary, , score (115)., , outcome of all-cause mortality or cardiovascular, , The FREEDOM trial compared CABG and PCI with, , rehospitalization (121)., , drug-eluting stents in 1,900 patients. After 5 years,, , No RCT has been conducted to determine whether, , CABG was superior to PCI on a combined endpoint of, , CABG or PCI offers greater benefit to patients with, , all-cause mortality, MI, and stroke across patients, , severe CAD and left ventricular dysfunction, because, , with low, intermediate, and high SYNTAX scores,, , these patients were excluded from the SYNTAX trial, , suggesting that these scores should not be used to, , and other RCTs. A recent network meta-analysis of, , guide choice of revascularization in patients with, , randomized and observational studies demonstrated, , diabetes (117)., , that CABG was associated with lower rates of mor-, , The results of these trials have been further, , tality, cardiac death, MI, and repeated revasculariza-, , confirmed by meta-analysis (118) as well as real-world, , tion compared with PCI (122). Analysis of a large, , data from a large administrative database (119),, , clinical database demonstrated that CABG was asso-, , demonstrating the superiority of CABG over PCI in, , ciated with a reduction in a composite of death, MI, or, , diabetics, , current, , stroke after nearly 4 years compared with PCI in pa-, , guidelines from Europe (51) and the United States, , tients with moderate (LVEF $35% and #45%) and, , (103) give CABG class IA and IIa/B recommendation,, , severe (LVEF #35%) left ventricular dysfunction, but, , respectively, in patients with diabetes and multi-, , there was no difference in patients with mild, , vessel CAD., , dysfunction (LVEF $45% and #55%) (123)., , LEFT, , with, , multivessel, , VENTRICULAR, , CAD., , Thus,, , DYSFUNCTION. The, , STICH, , The, , STICH, , trial, , also, , provided, , important, , (Surgical Treatment for Ischemic Heart Failurel, , hypothesis-generating data that mitral valve repair at, , NCT00023595) trial was designed to evaluate whether, , the time of CABG in patients with heart failure and, , CABG afforded any benefit over optimal medical, , moderate or worse ischemic mitral regurgitation may, , therapy alone in patients with left ventricular, , improve survival (124). Those data generated a sub-, , dysfunction. The STICH trial randomized patients, , sequent RCT by the National Heart Lung and Blood, , with CAD amenable to CABG and left ventricular, , Institute, , ejection fraction (LVEF) #35% to optimal medical, , Network (CTSN) in which patients with moderate, , therapy alone or CABG. Among patients eligible for, , (NHLBI), , Cardiothoracic, , Surgical, , Trials, , ischemic regurgitation to CABG alone (n ¼ 151) or CABG, , CABG, some were considered to be candidates for, , plus mitral valve repair (n ¼ 150) were randomized, , surgical ventricular reconstruction (SVR) if they had, , (125). Because of the relatively small sample size in the, , dominant anterior left ventricular akinesia or dyski-, , trial, to facilitate adequate power, a primary endpoint, , nesia. Therefore, 2 randomized comparisons were, , of left ventricular reverse remodeling was selected, , performed and reported separately: medical therapy, , instead of a clinical endpoint. The addition of mitral, , alone versus medial therapy and CABG without SVR, , valve repair to CABG was not associated with any dif-, , (hypothesis 1) and medical therapy plus CABG with or, , ference in left ventricular reverse remodeling after 2, , without SVR (hypothesis 2)., , years despite a more durable reduction in mitral, , The first STICH study randomized patients with, , regurgitation (125). Moreover, there were no detectible, , CAD and left ventricular dysfunction to best medical, , benefits regarding survival or rehospitalization, and, , therapy alone (n ¼ 602) or medial therapy plus CABG, , patients undergoing mitral valve repair were at, , without SVR (n ¼ 610). After 5 years, patients, , increased risk for adverse neurologic events and sup-, , assigned to CABG had lower rates of cardiovascular, , raventricular arrhythmias., , mortality and all-cause mortality or cardiovascular-, , STABLE ISCHEMIC HEART DISEASE. The first RCTs, , related rehospitalization compared with patients, , involving CABG eventually demonstrated a long-term, , assigned to medical therapy alone, although there, , survival advantage conferred by surgery over medical, , was no difference in the primary outcome of all-cause, , therapy alone (37), but those trials were performed in, , mortality. After 10 years, a benefit of CABG for the, , an era without the widespread availability of optimal, , primary end point of all-cause mortality was evident,, , medical therapy including statins. This raises the, , and CABG also had lower cardiovascular mortality, , issue of whether improvements in medical manage-, , and all-cause mortality or rehospitalization (120)., , ment may have closed the outcomes difference with, , The second STICH study randomized patients with, , surgical revascularization. Similarly, no RCTs have, , CAD and left ventricular dysfunction to best medical, , definitively proven that PCI affords a survival benefit, , therapy and CABG with SVR (n ¼ 501) or without SVR, , over medical therapy in patients with stable ischemic, , (n ¼ 499). After 4 years, there was no difference, , heart disease (126)., , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved.

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Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , The contemporary ISCHEMIA (International Study, , world implementation of CABG and its outcomes., , of Comparative Health Effectiveness With Medical, , The, , and Invasive Approaches; NCT01471522) trial was, , launched in response to a 1986 report from the federal, , STS, , Adult, , Cardiac, , Surgery, , Database, , was, , designed in part to address this knowledge gap (127)., , Health Care Financing Administration agency that, , Patients with stable CAD and moderate or severe, , had published poorly adjudicated and improperly, , ischemia on stress testing were randomized to best, , adjusted mortality data from administrative claims, , medical therapy alone (n ¼ 2,591) or an invasive, , for CABG in a manner that surgical leaders thought, , approach with angiography and revascularization, , was misleading to the public (130). In its most recent, , when feasible in addition to best medical therapy, , report, the STS database counted 1,088 participating, , (n ¼ 2,588). It is key to proper interpretation of the, , hospitals accounting for 3,036 surgeons from all 50, , ISCHEMIA trial to note that randomization was to, , states in the United States, representing an estimated, , medical therapy or coronary angiography, not medi-, , >95% of all cardiac procedures performed, as well as, , cal therapy versus revascularization (128). This, , 10 sites in Canada and 21 sites in other countries (131)., , nuance, , patients, , The data captured in the STS database have allowed, , assigned to angiography, only 80% were revascular-, , for the development of robust risk models to predict, , ized (and a minority of these patients [26%] under-, , likelihood of perioperative mortality and morbidity, , went CABG), while among those initially assigned, , based on preoperative risk factors (132) and have, , conservative management, 21% eventually under-, , facilitated, , went revascularization. Of note, patients with sig-, , CABG, many of which have been cited in this review., , is, , important, , because,, , among, , many, , high-quality, , papers, , evaluating, , nificant LM disease, LVEF #35%, New York Heart, , The STS database has also facilitated public, , Association functional class III or IV heart failure, , reporting of outcomes of CABG since 2010. Among, , symptoms, and or unacceptable angina despite, , programs that initially agreed to participate in public, , maximal medical therapy (ie, patients with clear in-, , reporting, higher CABG volumes and improved, , dications for CABG or, potentially, PCI) were excluded, , observed:expected outcomes ratios were evident, , from enrollment. After a median of 3.2 years, the, , compared with those not voluntarily reporting their, , initial angiography approach did not reduce rates of, , results (133). Public reporting of outcomes data for, , ischemic cardiovascular events or all-cause mortality, , CABG (and other cardiac procedures) will hopefully, , compared with an initial conservative strategy., , inform patients about high-quality CABG centers that, , However, there was a significant improvement in, , use a continuous cycle of quality improvement to, , quality of life as measured by angina-related health, , ensure that optimal coronary revascularization stra-, , status among patients assigned to the interventional, , tegies are used in each case (28)., , arm, a difference that was most evident in patients, with “acceptable” angina compared with those with, no angina symptoms at baseline (129). Notably, the, survival benefit of CABG over medical therapy in the, RCTs from the 1970s was not evident until at least 7, years, , after, , randomization;, , therefore,, , additional, , follow-up of ISCHEMIA patients is essential to, determine whether up-front angiography and revascularization when indicated affords any survival, benefit over the very long-term. As noted above,, however, the ISCHEMIA trial should not be interpreted as a direct comparison of revascularization, and best medical therapy, even after long-term, follow-up becomes available., , CORONARY ARTERY SURGERY AS, A SUBSPECIALTY, CABG is the operation that catalyzed the field of cardiac surgery and remains the core operation performed in the specialty. It continues to be the most, common operation performed in cardiac surgery,, representing 55% of all cardiac operations, and is, arguably the most technically demanding operation, in the specialty. But CABG continues to be viewed by, surgeons as a “generalist” procedure that most or all, cardiac surgeons perform while also performing many, other operations also in the course of routine practice. This approach is counter to the trends in per-, , ASSESSMENT AND REPORTING OF, , formance of other procedures in cardiac surgery. The, , CABG OUTCOMES, , specialty has developed surgeons who specialize in, mitral valve surgery, aortic valve surgery, thoracic, , Large clinical outcomes databases have served an, , aortic procedures, atrial fibrillation surgery, and heart, , important role in providing high-quality data to, , transplantation/mechanical circulatory support. But, , evaluate outcomes of CABG. When coupled with, , very few individuals call themselves “coronary, , advanced statistical modeling, databases provide, , revascularization specialists” and focus specifically, , robust data with risk adjustments to evaluate real-, , on CABG. As a consequence, procedure performance, , Downloaded for Abhishek Srivastava ([email protected]) at Fortis Escorts Heart Institute and Research Centre from ClinicalKey.com by, Elsevier on November 03, 2021. For personal use only. No other uses without permission. Copyright ©2021. Elsevier Inc. All rights reserved., , 379

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380, , Mack et al., , JACC VOL. 78, NO. 4, 2021, JULY 27, 2021:365–83, , Surgical Coronary Revascularization, , and outcomes have not substantially changed over, , of CABG. The management of postoperative atrial, , the past two decades. This has led to an effort to treat, , fibrillation (POAF), which occurs in 20% to 25% of, , coronary artery surgery as a subspecialty within car-, , patients after CABG, continues to be a vexing prob-, , diac surgery and train coronary revascularization, , lem. An ongoing pivotal trial using botulinum toxin to, , specialists (134). Implicit in the argument for more, , block the autonomic ganglionic plexi and lessen the, , focused subspecialization is that CABG outcomes are, , incidence of POAF (NOVA Trial; NCT03779841) is, , influenced by a volume-outcome relationship, ie, the, , currently, , enrolling., , more one does a procedure, the better one becomes at, , the, , of, , performing it, thus resulting in better outcomes. With, , PACes (POAF after CABG: the Anticoagulation for New, , specialists focused specifically on coronary revascu-, , Onset Post-operative Atrial Fibrillation After CABG;, , larization, early operative outcomes should improve, , NCT04045665) trial is in the early stages of enroll-, , and other aspects of the operation may be advanced,, , ment by the NHLBI CTSN. Also forthcoming are the, , including multiarterial grafting, minimal-access ap-, , outcomes of trials examining the role of platelet, , proaches, and revascularization heart team strategies, , reactivity to determine the timing of CABG after, , and collaborations. Whether this effort will gain mo-, , STEMI in patients on antiplatelet therapy. Other, , mentum, , ongoing trials continue to examine adjuvant therapy, , and, , become, , widely, , adopted, , remains, , uncertain., , Although, , and clinical questions surrounding coronary revascularization that need to be answered, some of which, are in the process of being addressed. With the, limited adoption of multiarterial grafting, the search, more, , trials, in, , are, , examining, , patients, , with, , durable, , additional, , comparative, , effectiveness, , studies of CABG and PCI continue to be discussed,, , There are a large number of remaining evidence gaps, , a, , Other, , anticoagulation, , to increase graft patency, including evolocumab., , FUTURE DIRECTIONS, , for, , role, , bypass conduit continues., , The VEST (Venous Graft External Support Trial;, NCT03209609) is an RCT examining the possible, benefit of external nitinol mesh scaffolding to sup-, , including latest-generation stents and CABG techniques, particularly in diabetics, none are forthcoming soon. As surgical coronary revascularization is, now approaching the 60th anniversary of its widespread introduction into clinical practice, it continues, to maintain an important role in the revascularization, of patients with complex coronary artery disease., , FUNDING SUPPORT AND AUTHOR DISCLOSURES, , port saphenous vein grafts and prevent intimal hy-, , The authors have reported that they have no relationships relevant to, , perplasia (Figure 2D). Results of this trial, with the, , the contents of this paper to disclose., , primary endpoint of minimal luminal diameter obtained with the use of intravascular ultrasound at 1, , ADDRESS, , year, will be available in 2021. Other unanswered, , Mack, Baylor Scott and White Health, 1100 Allied, , FOR, , CORRESPONDENCE:, , questions include the role a functional flow reserve in, , Drive, Plano, Texas 75093, USA. E-mail: michael., , selecting coronary arteries to be bypassed at the time, , [email protected]. 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